Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention

Abstract

Cells have evolved a complex molecular network, collectively called the protein homeostasis (proteostasis) network, to produce and maintain proteins in the appropriate conformation, concentration and subcellular localization. Loss of proteostasis leads to a reduction in cell viability, which occurs to some degree during healthy ageing, but is also the root cause of a group of diverse human pathologies. The accumulation of proteins in aberrant conformations and their aggregation into specific beta-rich assemblies are particularly detrimental to cell viability and challenging to the protein homeostasis network. This is especially true for bacteria; it can be argued that the need to adapt to their changing environments and their high protein turnover rates render bacteria particularly vulnerable to the disruption of protein homeostasis in general, as well as protein misfolding and aggregation. Targeting bacterial proteostasis could therefore be an attractive strategy for the development of novel antibacterial therapeutics. This review highlights advances with an antibacterial strategy that is based on deliberately inducing aggregation of target proteins in bacterial cells aiming to induce a lethal collapse of protein homeostasis. The approach exploits the intrinsic aggregation propensity of regions residing in the hydrophobic core regions of the polypeptide sequence of proteins, which are genetically conserved because of their essential role in protein folding and stability. Moreover, the molecules were designed to target multiple proteins, to slow down the build-up of resistance. Although more research is required, results thus far allow the hope that this strategy may one day contribute to the arsenal to combat multidrug-resistant bacterial infections.

Is It Possible to Create Antimicrobial Peptides Based on the Amyloidogenic Sequence of Ribosomal S1 Protein of P. aeruginosa?

“…However, separate studies have examined bacterial amyloids [33]: amyloidogenesis of a prion-like protein was experimentally detected in E. coli using a fluorescent dye, and the RepA-WH1 protein formed cytotoxic aggregates that prevent bacterial growth [34]. The special attention should be paid to the use of the amyloidogenic properties of bacterial proteins for targeted protein aggregation [35]. The development of synthetic amyloidogenic peptides has been shown to be a promising approach to combat pathogenic bacteria [36,37].…”

“…The development of synthetic amyloidogenic peptides has been shown to be a promising approach to combat pathogenic bacteria [36,37]. At the same time, it should be borne in mind that bacteria have different mechanisms of counteracting protein aggregation, for example, by directing amyloids into inclusion bodies [35]. In addition, some bacteria are capable of using amyloids and amyloid-like protein structures in order to form biofilms [38,39].…”

Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein

“…A characteristic of protein aggregation is a phenomenon called "seeding", in which the rate of aggregation of monomeric protein is increased by adding preformed aggregates, typically fragmented mature fibrils of the same protein, to the monomer solution ( 33 ). This process is sequence specific, meaning that it is most efficient when the preformed aggregates are homologous to the monomeric protein ( 6 , 34 ). Since TPA relies on the ability of the Pept-ins to induce the aggregation of the full-length protein, we evaluated the seeding capacity of the aggregating Pept-ins on purified KRAS protein under native conditions.…”

Bacillus subtilis forms twisted cells with cell wall integrity defects upon removal of the molecular chaperones DnaK and trigger factor

“…Targeting proteostasis has been proposed as a novel antibacterial strategy ( Khodaparast et al, 2021 ). Based on the reduced tolerance of the dnaK tig double mutant to cell wall antibiotics, inducing proteostasis collapse while administering cell wall antibiotics may be an attractive combined strategy to increase treatment efficacy in the fight of pathogens.…”